Oncotarget

Research Papers:

Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport

Raghavendra Gowda, Gajanan S. Inamdar, Omer Kuzu, Saketh S. Dinavahi, Jacek Krzeminski, Madhu Babu Battu, Sreedhara R. Voleti, Shantu Amin and Gavin P. Robertson _

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Oncotarget. 2017; 8:28260-28277. https://doi.org/10.18632/oncotarget.16002

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Abstract

Raghavendra Gowda1,5,6,7, Gajanan S. Inamdar1, Omer Kuzu1, Saketh S. Dinavahi1, Jacek Krzeminski1, Madhu Babu Battu8, Sreedhara R. Voleti8, Shantu Amin1, Gavin P. Robertson1,2,3,4,5,6,7

1Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA

2Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA

3Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA

4Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA

5The Penn State Melanoma and Skin Cancer Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA

6Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA

7Foreman Foundation for Melanoma Research Laboratory, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA

8Drug Discovery Research Laboratory, INDRAS Private Limited, Hyderabad, India 500040

Correspondence to:

Gavin P. Robertson, email: gpr11@psu.edu

Keywords: melanoma, leelamine, abietic acid, structure-activity relationship, AKT

Received: December 23, 2016     Accepted: February 23, 2017     Published: March 08, 2017

ABSTRACT

Leelamine is an anticancer chemotherapeutic agent inhibiting intracellular cholesterol transport. Cell death mediated by leelamine occurs due to the lysosomotropic property of the compound, its accumulation in the lysosome, and inhibition of cholesterol transport leading to lack of availability for key processes required for functioning of cancer cells. The present study dissects the structure-activity-relationship of leelamine using synthesized derivatives of leelamine and abietic acid, a structurally similar compound, to identify the moiety responsible for anti-cancer activity. Similar to leelamine, all active derivatives had an amino group or a similar moiety that confers a lysosomotropic property to the compound enabling its accumulation in the lysosome. Active derivatives inhibited intracellular cholesterol transport and hindered xenografted melanoma tumor development without obvious systemic toxicity. In silico studies suggested that active derivatives accumulating in lysosomes bound to NPC1, a protein responsible for cholesterol export from the lysosome, to inhibit its activity that then caused accumulation, and lack of cholesterol availability for other key cellular activities. Thus, active derivatives of leelamine or abietic acid maintained lysosomotropic properties, bound to NPC1, and disrupted cellular cholesterol transport as well as availability to retard tumor development.


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